The early events of HIV-1 infection present an attractive target for development of prophylactic approaches. The goal is to prevent HIV-1 infection before the virus is established instead of trying to treat a systemic and progressive disease with the added complexity of acquired drug resistance. The vast majority of new HIV-1 infections in the future will be acquired through sexual transmission. Microbicides that inactivate HIV-1 at the sites of transmission have the potential to interrupt sexual transmission, which is relatively ineffective and typically involves few successful events. To date, the majority of failed microbicides have been non-specific surfactant-based molecules. The studies described in this proposal are therefore focused on the early events of HIV-1 infection for the ultimate goal of identifying a potent agent that specifically blocks HIV-1 transmission. Three distinct and innovative technologies that have recently been validated successfully in model systems will be used to investigate strategies to block entry of HIV-1 infection by amplifying the potency of known small molecules that specifically bind gp120. Two chemical approaches will be evaluated to test which one will yield initial proof-of-concept using a humanized mouse model for HIV-1 infection. We propose to investigate strategies to block entry of HIV-1 using innovative technologies that have been validated successfully in model systems. Using these approaches, we will be able to identify novel dendrimeric small molecules that specifically bind a conserved pocket in HIV-1 gp120, blocking HIV-1 entry. These effective approaches should identify molecular scaffolds that may potentially be used as microbicides to combat HIV-1 transmission.